Improved Biomedical Polyurethanes

Abstract

The invention is directed to biomedical polyurethanes. The invention is particularly directed to biomedical polyurethanes with improved biodegradability and to an improved preparation of the biomedical polyurethanes. In particular the present invention provides a biomedical polyurethane having the formula (A-B-C-B).sub.n, wherein A denotes a polyol, B denotes a diisocyanate moiety, C denotes a diol component and n denotes the number of recurring units, and wherein the B-C-B segment is bioresorbable.

Claims

1.-16. (canceled)

17. Biomedical polyurethane having the formula A-B-C-B.sub.n, wherein A denotes a polyol comprising a prepolymer that is at least partially based on a random copolyester, B denotes a diisocyanate moiety, C denotes a diol component and n denotes the number of recurring units, wherein the B-C-B segment is bioresorbable, wherein at least one of, preferably both the diisocyanate moieties (B) in B-C-B have a different length than the diol component (C), and wherein the B-C-B segment is based on two diisocyanate units and comprises more than 14 linear carbon atoms in the backbone.

18. Biomedical polyurethane according to claim 17, wherein the B-C-B segment has a multiform block length.

19. Biomedical polyurethane according to claim 17, wherein the B-C-B segment comprises more than 16 linear carbon atoms in the backbone.

20. Biomedical polyurethane according to claim 18, wherein less than 95%, preferably less than 80%, more preferably less than 70%, most preferably less than 60% of the B-C-B segments have the same length.

21. Biomedical polyurethane according to any of the previous claims, wherein B is at least partially based on a linear or branched C.sub.4 to C.sub.11 alkyl diisocyanate, preferably selected from the group consisting of 1,4-butane diisocyanate (BDI), 1,5-pentane diisocyanate (PDI), 1,6-hexyl diisocyanate (HDI), 1,7-heptyl diisocyanate (HpDI), 1,8-octyl diisocyanate (ODI), 1,9-nonyl diisocyanate (NDI), 1,10-decyl diisocyanate (DDI), methylene bis(4-cyclohexylisocyanate), 2,6-diisocyanatohexanoate and esters thereof (L-lysine diisocyanate, LDI), 5-isocyanate-1-(isocyanomethyl)-1,3,3-trimethylcyclohexane (isophorondiisocyanate, IPDI) and combinations thereof.

22. Biomedical polyurethane according to any of the previous claims, wherein C is at least partially based on C.sub.4 to C.sub.11 alkyl diols, preferably selected from the group consisting of glycol, diethylene glycol, 1,4-butane diol (BDO), 1,5-pentane diol (PDO), 1,6-hexyl diol (HDO), 1,7-heptyl diol (HpDO), 1,8-octyl diol (ODO), 1,9-nonyl diol (NDO), 1,10-decyl diol (DDO), N-methyl diethanolamine (N-MDEA), 2,2-bis(hydroxymethyl)propanoic acid, tartartic acid, polyethylene glycol, polycaprolactone, poly lactide and combinations thereof.

23. Biomedical polyurethane according to any of the previous claims, wherein C is at least partially based on a molecule comprising three or more alcohol groups, preferably a triol, more preferably triethanol amine or glycerol, in an amount of 0.01 to 10 mol %.

24. Biomedical polyurethane according to any of the previous claims, wherein the copolyester is based on lactide, glycolide, trimethylene carbonate and/or -caprolactone.

25. Biomedical polyurethane according to claim 24, wherein the random copolyester is at least partially based on 5 to 95, preferably 40 to 60 mol % of lactide and 5 to 95, preferably 40 to 60 mol % -caprolactone.

26. Biomedical polyurethane according to any of the previous claims, for use in a method of the treatment of nasal wounds, nerves, meniscal injuries, skin and/or veins.

27. Medical device such as a foam or a sheet, comprising the biomedical polyurethane according to any of the previous claims.

28. Method for the preparation of a biomedical polyurethane in accordance with any of the previous claims, said method comprising the step of: i) reacting the polyol A with the diisocyanate B to form an isocyanate terminated polyol B-A-B, followed by; ii) determining the amount of isocyanate groups [RNCO], followed by; iii) reacting the isocyanate terminated polyol B-A-B with the diol component C to form the biomedical polyurethane having the formula A-B-C-B.sub.n.

29. Method according to claim 28, wherein the amount of the isocyanate groups [RNCO] is monitored during step iii), preferably by using FT-IR.

30. Method according to any of the claim 28 or 29, wherein the diol component C comprises two or more different diol compounds that differ in their respective lengths such that the B-C-B segment in the biomedical polyurethane has a multiform length.

31. Method according to any of the claims 28-30, further comprising a step of forming a medical device such as a foam or a sheet of the biomedical polyurethane.

Description

EXAMPLE 1

[0066] A polyol (50 g, 0.025 mol, 2000 g/mol) was synthesized from DL-lactide and -caprolactone using PEG1000 (i.e. PEG having an average. molecular weight of 1000 g/mol) as an initiator and stannous octoate as a catalyst at a temperature of 140 C. for 14-17 days under nitrogen atmosphere. The polyol was subsequently reacted with 3.5 g (0.05 mol, 2 eq.) of butanediisocyanate (BDI). After complete conversion (within 1 h), the concentration isocyanates ([NCO]) was determined using FT-IR. This [NCO] is used to determine the amount of chain extender diol component (1,6-hexanediol) which needs to be added to obtain the 3-block polyurethane. The following equation was used:

[00001]$\mathrm{Mass}.Math..Math.\mathrm{HDO}\left(\mathrm{mg}\right)=\frac{\left[\mathrm{NCO}\right]\left(m_{\mathrm{polymer}}+m_{\mathrm{BDI}}\right)M_{\mathrm{HDO}}}{2}0.98$

[0067] 1,4-dioxane was added as the solvent (ratio 1:1) and the reaction mixture was heated to 90 C. The reaction mixture became viscous over time and the [NCO] was monitored during the reaction using FT-IR. After complete conversion of the available NCO groups, the reaction mixture was diluted with 1,4-dioxane. The obtained polymer could be processed into foams by freeze-drying or into sheets/tubes using solvent casting.

EXAMPLE 2

[0068] A polyol (50 g, 0.025 mol, 2000 g/mol) was synthesized from DL-lactide and -caprolactone using PEG1000 as an initiator and stannous octoate as a catalyst at a temperature of 140 C. for 14-17 days under nitrogen atmosphere. Gelpermeation chromatography (GPC) and .sup.1H-NMR showed complete conversion of the monomers. The polyol was subsequently reacted with 3.5 g (0.05 mol, 2 eq.) of butanediisocyanate (BDI). After complete conversion (within 1 h), the [NCO] was determined using FT-IR. This [NCO] was used to determine the amount of chain extender diol (1,8-octanediol) component which needs to be added to obtain the 3-block polyurethane. The following equation was used:

[00002]$\mathrm{Mass}.Math..Math.\mathrm{HDO}\left(\mathrm{mg}\right)=\frac{\left[\mathrm{NCO}\right]\left(m_{\mathrm{polymer}}+m_{\mathrm{BDI}}\right)M_{\mathrm{HDO}}}{2}0.98$

[0069] 1,4-dioxane was added as the solvent (ratio 1:1) and the reaction mixture was heated to 90 C. The reaction mixture became viscous over time and the [NCO] was monitored during the reaction using FT-IR. After complete conversion of the available NCO groups, the reaction mixture was diluted with 1,4-dioxane. The obtained polymer could be processed into foams by freeze-drying or into sheets/tubes using solvent casting.

EXAMPLE 3

[0070] A prepolymer (50 g, 0.025 mol, 2000 g/mol) was synthesized from DL-lactide and -caprolactone using PEG1000 as an initiator and stannous octoate as a catalyst at a temperature of 140 C. for 14-17 days under nitrogen atmosphere. Gelpermeation chromatography (GPC) and .sup.1H-NMR showed complete conversion of the monomers. The prepolymer was subsequently reacted with 8.41 g (0.05 mol, 2 eq.) of hexanediisocyanate (HDI). After complete conversion (within 1 h), the [NCO] was determined using FT-IR. This [NCO] was used to determine the amount of chain extender diol component (BDO) which needs to be added to obtain the 3-block polyurethane. The following equation was used:

[00003]$\mathrm{Mass}.Math..Math.\mathrm{HDO}\left(\mathrm{mg}\right)=\frac{\left[\mathrm{NCO}\right]\left(m_{\mathrm{polymer}}+m_{\mathrm{BDI}}\right)M_{\mathrm{HDO}}}{2}0.98$

[0071] 1,4-dioxane was added as the solvent (ratio 1:1) and the reaction 5 mixture was heated to 90 C. The reaction mixture became viscous over time and the [NCO] was monitored during the reaction using FT-IR. After complete conversion of the available NCO groups, the reaction mixture was diluted with 1,4-dioxane. The obtained polymer could be processed into foams by freeze-drying or into sheets/tubes using solvent casting.

EXAMPLE 4

[0072] A series of polyurethanes was prepared in a method similar to that of Examples 1-3. The same prepolymer was used, but different diisocyanate moieties and/or diol components were used.

[0073] Characterization

[0074] The properties of the prepared foams are provided in Tables 1 and 2. The intrinsic viscosity (IV) was measured using a falling ball microviscometer (Anton Paar) using a one-point measurement according to the Solomon-Ciuta approximation in chloroform as a solvent at 25 C. The thermal properties of the polymer where determined using a Q2000 (TA Instruments). The mechanical properties were determined using an Instron Tensile tester. The foam absorbance was determining the weight of a foam (3.5 wt % obtained by freeze-drying) with the weight of the same foam soaked in water (depicted as x times initial weight). The foam absorbance rate (mL/sec) was determined by measuring the weight of the foam after predetermined time intervals in a petri dish containing water.

[0075] Calorimeter studies were carried out with the Q2000. The scanning rate was 10 C. per minute. The results are provided in FIGS. 1 and 2.

TABLE-US-00001 TABLE 1 BDI-BDO-BDI- B-C-B HDI-HDO-HDI BDO-BDI BDI-BDO-BDI Tg ( C.) 37.7 39.7 34.1 Tm ( C.) 108.3 96.0 Foam absorbance 18.6 17.5 (x initial weight) Foam absorption 183 124 rate (mL/sec) Mw (g/mol) 66200 56400 Mn (g/mol) 49900 35300 IV (dL/g) 1.0 1.8 Modulus (MPa) 12.5 37.4

TABLE-US-00002 TABLE 2 HDI- HDI- BDI- BDI- B-C-B ODO-HDI BDO-HDI ODO-BDI HDO-BDI Foam absorbance 19.2 17.6 19.4 17.2 (x initial weight) Foam absorption rate 267 199 286 254 (mL/sec) Mw (g/mol) 61400 57700 63100 48800 Mn (g/mol) 44200 37400 41000 31300 IV (dL/g) 1.00 0.89 1.09 0.77 Modulus (MPa) 16.5 15.8 15.4 9.65

[0076] Method for In Vitro Degradation

[0077] The in vitro degradation studies of the prepared polyurethanes were performed in test tubes using Sorensen buffer solution with a pH of 7.4 as the degradation medium, kept in an incubator at 37 C. Sorensen buffer solution was prepared by mixing 18.2 wt % KH.sub.2PO.sub.4 (0.012 M) with 81.8 wt % NaH.sub.2PO.sub.4 (0.055 M). The buffer solutions were poured into 100 mL bottles. A polymer sample was added to each bottle and the sample was subsequently incubated for specific time periods. After time periods of 0, 0.5, 1, 3, 5, 7, 16, 44, 48, 72, 96, 168, 336, 672 and 2016 h, samples were removed from the bottles which were stored in the incubator, washed thoroughly with distilled water (510 mL) onto a 0.45 m filter paper, frozen in a freezer overnight, freeze-dried for 24 h and the remaining sample was characterized with respect to thermal properties, weight, absorption, compression, IV and molecular weight distribution.

[0078] The results are provided in FIGS. 3 and 4.

EXAMPLE 5

[0079] A series of polyurethanes was prepared with a procedure similar to Example 2. The same prepolymer and diisocyanate (BDI) were used, but mixtures of diol components (BDO-BDI-BDO and N-MDEA in ratios of 50/50 to 100/0) were used to prepare polyurethanes comprising urethane segments having a pluriform length.

[0080] The biodegradability of the resulting polyurethanes was determined in a method for in vitro degradation as described in Example 4.

[0081] The results are provided in FIG. 5.